Abstracts

Rationale: Epilepsy is a common neurological disorder and affects over 70 million people worldwide. Despite the availability of over 20 anti-epileptic drugs (AEDs) with diverse molecular targets for the treatment of epileptic seizures, approximately one-third of patients with epilepsy fail to achieve seizure control. We previously demonstrated that NCC-1566, a first in class novel small molecule inwardly rectifying potassium channels (Kir) activator shows an excellent in vivo anti-convulsive effect in various rodent models of acute seizure, an anti-epileptic activity in a mesial temporal lobe epilepsy model, and a wider safety margin than carbamazepine in a rota-rod test. Subsequent analyses revealed that NCC-1566 was also effective in the rat amygdala kindling model and the DBA/1 mouse SUDEP model (effective dose = 55 mg/kg and 30 mg/kg, respectively). However, it was unclear whether NCC-1566 would be effective in the 6 Hz seizure test, a model of therapy-resistant seizures. The present study seeks to evaluate the anti-seizure potential of Kir activator by the combined administration of NCC-1566 with classic AEDs in a widely employed preclinical model of pharmacoresistant seizures (Epilepsy Research 2001; 47(3); 217).

Methods: The anti-convulsant efficacy of a selective Kir activator (NCC-1566) was evaluated alone and in combination with one of the current gold standard drug levetiracetam in the mouse 6 Hz model. Briefly, mice received corneal stimulations of 32 or 44 mA/0.2 ms at 6 Hz for 3 s. Animals exhibited immobility associated with rearing, automatisms, forelimb clonus, twitching of the vibrissae, and sometimes Straub tail. Animals not displaying any of the behaviors noted above during 1-min observation were considered “protected”.

Results: In the 6 Hz model at 32 mA stimulus intensity, median effective dose (ED50) values of NCC-1566 and levetiracetam were 13 mg/kg and < 60 mg/kg, respectively. At 44 mA stimulus intensity, ED50 values of NCC-1566 and levetiracetam were 41 mg/kg and >60 mg/kg, respectively. Combined administration of levetiracetam at a moderate effective dose (60 mg/kg) and NCC-1566 at various subprotective doses elicited the effective protection that could not be achieved by the administration of each alone. The ED50 for NCC-1566 combination with levetiracetam was 3 mg/kg, suggesting the synergistic potential of NCC-1566 and levetiracetam in the 6Hz model at 44 mA stimulus intensity.

Conclusions: These studies demonstrate a potential synergistic effect of Kir-acting compounds in combination with levetiracetam in a model of pharmacoresistant seizures. Since seizure suppression by Kir activation is a novel mechanism of action, it may be suitable for use in combination with any AEDs currently in clinical use. Therefore, Kir activators could be highly attractive candidates to provide promising treatment options, especially add-on therapies, for patients with refractory epilepsy.

Funding: Please list any funding that was received in support of this abstract.: This study is funded by Nissan Chemical Corporation. All authors are employed by Nissan Chemical Corporation.